Mutations in Sodium-Channel Gene SCN9A Cause a Spectrum of Human Genetic Pain Disorders Joost P.H

Science in medicine Mutations in sodium-channel gene SCN9A cause a spectrum of human genetic pain disorders Joost P.H. Drenth1 and Stephen G. Waxman2,3

1Department of Medicine, Division of Gastroenterology and Hepatology, University Medical Center St. Radboud, Nijmegen, The Netherlands. 2Department of Neurology, Yale University School of Medicine, New Haven, Connecticut, USA. 3Center for Neuroscience and Regeneration Research, West Haven VA Medical Center, West Haven, Connecticut, USA.

The voltage-gated sodium-channel type IX α subunit, known as Nav1.7 and encoded by the gene SCN9A, is located in peripheral neurons and plays an important role in action potential produc- tion in these cells. Recent genetic studies have identified Nav1.7 dysfunction in three different human pain disorders. Gain-of-function missense mutations in Nav1.7 have been shown to cause primary erythermalgia and paroxysmal extreme pain disorder, while nonsense mutations in Nav1.7 result in loss of Nav1.7 function and a condition known as channelopathy-associated insensitivity to pain, a rare disorder in which affected individuals are unable to feel physical pain. This review highlights these recent developments and discusses the critical role of Nav1.7 in pain sensation in humans.

Pain is one of the most pervasive symptoms in clinical medicine; type IX α subunit (SCN9A, referred to herein as Nav1.7) as a key it occurs in a multitude of clinical conditions and is encountered player in three conditions in which recurrent pain or the inabil- by clinicians in every subspecialty. Yet treatment of chronic or ity to sense pain is a prominent symptom (3–8). These disorders recurrent pain remains challenging, in part because the thera- — primary erythermalgia (PE), paroxysmal extreme pain disorder peutic armamentarium is incomplete. Hopefully, this will change (PEPD), and channelopathy-associated insensitivity to pain (CIP) as a result of increased understanding of the molecular basis of — are typified by very different pain phenotypes. Remarkably, pain. Over the past several years, elucidation of the genetic defects recent work has shown that different types of channelopathies underlying three monogenic pain disorders has provided impor- (diseases caused by disturbed function of ion channel subunits tant insights about human pain and its molecular substrates. or the proteins that regulate them), all involving the same Nav1.7 Here, we briefly review these recent advances. sodium channel, underlie all three of these disorders (3–8). These discoveries allow better understanding not only of the molecular A genetic basis for pain pathogenesis of these particular disorders but also of the molecu- The unraveling of the human genome may allow us to compare lar pathophysiology of pain (9). variations at the genetic level with interindividual differences in pain thresholds and pain perception. Most studies in the past have Sodium channels focused on genetic polymorphisms that might be responsible for Voltage-gated sodium channels play a critical role in the generation interindividual differences in pain perception. For example, a and conduction of action potentials and are thus important for common functional SNP (V58M) in the catechol-O-methyltransfer- electrical signaling by most excitable cells (10, 11). Sodium chan- ase (COMT) gene modifies pain sensitivity (1). COMT has broad nels are integral membrane proteins and are comprised of a large α biological functions, including the metabolism of catecholamines, subunit, which forms the voltage-sensitive and ion-selective pore, such as neurotransmitters, that modulate neuronal cell signaling. and smaller auxiliary β subunit(s) that can modulate the kinetics Individuals homozygous for the Val genotype are less sensitive to and voltage dependence of channel gating (12). To date, we know pain compared with those with Met homozygosity (1); however, of 9 isoforms of the sodium-channel α subunit (Nav1.1–Nav1.9), the differences in pain sensitivity between groups are relatively each with a unique central and peripheral nervous system distribu- subtle. A more dramatic set of observations has been reported in tion (10). Four closely related sodium channels (Nav1.1, -1.2, -1.3, studies of rare Mendelian disorders. Over a decade ago, mutations and -1.7) are encoded by a set of 4 genes (SCN1A, SCN2A, SCN3A, in the voltage-dependent calcium channel, P/Q type 1A α subunit and SCN9A, respectively) located within a cluster on chromosome (CACNL1A4) were identified in families with familial hemiplegic 2q24.3. Mutations in the genes encoding Nav1.1, -1.2, and -1.3 are migraine, a subtype of migraine with aura and paralysis (2). This responsible for a group of epilepsy syndromes with overlapping finding indicated that channel dysfunction could lead to human clinical characteristics but divergent clinical severity (13, 14). Here, disorders in which pain is a prominent symptom. More recent we focus on one of the α subunits, Nav1.7, because of its critical genetic studies have identified the voltage-gated sodium-channel role in pain sensation. Nav1.7 is encoded by SCN9A, a 113.5-kb gene comprising 26 exons (OMIM 603415) (Figure 1A). The encoded sodium channel is com- Nonstandard abbreviations used: CIP, channelopathy-associated insensitivity to posed of 1977 amino acids organized into 4 domains, each with 6 pain; DRG, dorsal root ganglion; Nav1.7, sodium channel encoded by SCN9A; PE, primary erythermalgia; PEPD, paroxysmal extreme pain disorder; SCN9A, voltage-gated transmembrane segments (15), and is predominantly expressed in sodium-channel type IX α subunit. the dorsal root ganglion (DRG) neurons and sympathetic gangli- Conflict of interest: The authors have declared that no conflict of interest exists. on neurons (16) (Figure 1B). Immunohistochemical studies show Citation for this article: J. Clin. Invest. 117:3603–3609 (2007). doi:10.1172/JCI33297. that Nav1.7 is present at the distal ends of the wire-like projections

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Figure 1 Mutations in the sodium-channel subunit Nav1.7 that are associated with the genetic pain disorders PE, PEPD, and CIP. (A) Nav1.7 is encoded by the 113.5-kb gene SCN9A, comprising 26 coding exons. The identity and location of known patient mutations in Nav1.7 that have been linked to PE (*), PEPD (^), and CIP (#) are shown. Note that the mutations are spread over the entire gene sequence; however, mutations linked to PEPD tend to be located closer to the 3′ end of the gene. (B) A schematic of the Nav1.7 sodium-channel subunit showing the 4 domains (D1–D4), each with 6 transmembrane segments. Locations of known mutations associated with genetic pain disorders PE, PEPD, and CIP are shown. COOH indicates the C-terminus of the peptide chain. HN indicates the N-terminus of the peptide chain.

of neurons known as neurites, close to the impulse trigger zone nel produces a rapidly activating and inactivating current that is where neuronal firing is initiated (16) (Figure 2). Interestingly, the sensitive to submicromolar levels of tetrodotoxin. This is in con- large majority of DRG neurons that express Nav1.7 are pain sens- trast with Nav1.8, which is also present within DRG neurons but ing (nociceptive), suggesting a role for this sodium channel in the is fairly resistant to tetrodotoxin. Nav1.7 appears to be important pathogenesis of pain (17). In addition to Nav1.7, Nav1.8 and Nav1.9 in early phases of neuronal electrogenesis. Nav1.7 is characterized are also predominantly present in small nociceptive sensory neu- by slow transition of the channel into an inactive state when it is rons and the nerve fibers emanating from them (18, 19). depolarized, even to a minor degree, a property that allows these channels to remain available for activation with small or slowly Physiology of Nav1.7 developing depolarizations, usually mimicked by electrophysiolo- In sensory neurons, multiple voltage-dependent sodium currents gists as ramp-like stimuli (20). Thus, Nav1.7 acts as a “threshold can be differentiated by their gating kinetics and voltage depen- channel” that amplifies small, subtle depolarizations such as gen- dence and can also be defined by their sensitivity to the voltage- erator potentials, thereby bringing neurons to voltages that stimu- gated sodium-channel blocker tetrodotoxin (12). The Nav1.7 chan- late Nav1.8, which has a more depolarized activation threshold and

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same researchers created mice deficient in both Nav1.7 and Nav1.8 (27). Mice deficient in Nav1.8 had deficits in sensing inflammatory pain (initiated by tissue damage/inflammation) and visceral pain (initiated by damage or injury to internal organs) but not neuropathic pain (28). The thermal pain threshold in mice deficient in both Nav1.7 and Nav1.8 mice was twice that of mice lacking only Nav1.7. There was no effect on induced neuropathic pain in the double knockouts, and the effect of the loss of Nav1.7 in raising the threshold for inflammatory pain was so overwhelm- ing that no additional effect of Nav1.8 deletion was seen. Collec- tively, these results clearly implicate Nav1.7 as a major sodium channel in peripheral nociception and suggest a functional link to Nav1.8. Although insightful, these data should be interpreted with caution, as direct evaluation of pain in mice is not possible. Instead, researchers rely on behavioral changes of animals such as signs of paw guarding, lifting, and limping. As a consequence, the relevance of the observed changes to human pain remains to be determined.

Figure 2 Primary erythermalgia Neuronal Nav1.7 channels. Nav1.7 (shown here in red after immuno- Primary or idiopathic erythermalgia (OMIM 133020) is an autoso- cytostaining with anti-Nav1.7 antibody; Alomone Reagents) within the mal dominant, inherited disorder. Clinically, PE is characterized by tip of a growing neurite from rat DRG neuron in culture. Image kindly provided by Joel A. Black, Department of Neurology, Yale University, attacks or episodes of symmetrical burning pain of the feet, lower New Haven, Connecticut, USA. legs, and sometimes hands, elevated skin temperature of affected areas, and reddened extremities (Figure 3) (29–32). PE is sometimes termed erythromelalgia, although some authorities reserve the latter which produces most of the transmembrane current responsible term for a condition that is caused by arteriolar inflammation as a for the depolarizing phase of action potentials (21). In this regard, result of platelet-rich thrombi in the end-arterial microvasculature, 9 Nav1.7 is poised as a molecular gatekeeper of pain detection at in which the platelet count is invariably elevated (> 400 × 10 cells/l) peripheral nociceptors. and a short course of aspirin brings swift relief (33). Platelet counts in PE are invariably normal, and aspirin is ineffective. Patients Inflammatory mediators and pain with PE usually develop symptoms within the first decade of life. A number of (inflammatory) mediators, such as prostaglandin As the disease progresses, the erythema can extend to the upper (22), adenosine (23), and serotonin (24), affect the electrophysio- legs, nose tip, earlobes, and chin. In the early years of the disease, logical properties of voltage-gated sodium channels. These media- the erythema is intermittent, but at later ages, the feet and hands tors increase the magnitude of the current, lead to activation of the may be constantly red and edematous. Complaints are provoked by channel at more hyperpolarized potentials, and enhance the rates of channel activation and inactivation. As a consequence, inflammation can sensitize nociceptive neurons. In an experimental model of inflammatory pain in which an irritant was injected into the hind paw in rats, Nav1.7 protein expression was upregulated within DRG neurons that project their axons to the inflamed area (25), a change that should increase excitability of these cells. Col- lectively, these data suggest that Nav1.7 contributes, at least in part, to pain associated with inflammation.

Animal studies of Nav1.7 To obtain insight into the physiological role of Nav1.7, Nassar et al. generated targeted knockout mice that lack Nav1.7 within nociceptive DRG neurons (26). Selective deletion of Nav1.7 in nociceptors from mice produces a phenotype in which heat-induced pain thresholds are minimally altered, there is no change in punctate mechanical pain threshold, and cold-evoked channel activity is unchanged. In contrast, there is a general failure to develop pain or hypersensitivity in response to inflammatory stimuli, while neuropathic pain (chronic pain resulting from injury to the nervous system) remains intact. These results are consistent with an important role of Nav1.7 in setting the inflammatory pain threshold. Figure 3 To assess the role of Nav1.7 further, especially in relation to other Red feet and lower legs in a patient with primary erythermalgia. Image sodium channels expressed in peripheral sensory neurons, the courtesy of The Erythromelalgia Association.

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Figure 4 Four clinical situations in which Nav1.7 channel activity is altered. PE and PEPD are autosomal dominant (AD) conditions, while CIP is inherited via an autosomal recessive (AR) trait. The mutations of the Nav1.7 channel grossly dictate that there is a gain of function (increased channel activity) in PE and PEPD, while Nav1.7 channel function is lost (absent) in CIP. The resultant phenotype is reflected in the lower row. In humans, the Nav1.7 mutations result in pain in the feet and hands (in PE) or ocular, mandibular, and/or rectal pain (in PEPD). In CIP, there is a loss of Nav1.7 channel function, resulting in an inability to register pain.

exercise, prolonged standing, or exposure to warmth, which usually hyperpolarizing shift in the voltage dependence of channel acti- compels patients not to wear socks or closed shoes, even during the vation, which allows the channel to be activated by smaller than winter. Patients typically sleep with uncovered feet, often cooled by normal depolarizations, thereby likely enhancing the activity of a fan. Cold alleviates these complaints, and some patients search Nav1.7. Most of the PE mutations also slow deactivation, thus for relief by immersion of feet in ice-cold water. The greatest threat keeping the channel open longer once it is activated (Figure 4). is that these actions can lead to trench foot with subsequent skin In addition, in response to a slow, depolarizing stimulus, most infections and even to limb amputations (34). mutant channels will generate a larger than normal inward sodi- A genome-wide linkage study in a large kindred of individuals um current. Repriming, which is the recovery from inactivation, with PE detected strong evidence for linkage with polymorphic has been shown to be faster for channels possessing specific PE markers on chromosome 2q (35). Haplotype analysis in four mutations (5, 6, 36, 38, 39, 42, 43). Each of these alterations in additional families confirmed the locus, and recombinant events activation and deactivation can contribute to the hyperexcitability defined the critical interval to 7.94 cM. Subsequent analysis of of pain-signaling DRG neurons expressing these mutant channels, another family allowed narrowing of the region to 5.98 cM (3). thus causing extreme sensitivity to pain (hyperalgesia) (44). While This interval contains five genes encoding sodium-channel α the expression of PE Nav1.7 mutations produces hyperexcitabil- subunits. After confirming the presence of this genetic interval in ity in DRG neurons, studies on cultured rat sympathetic ganglion two affected families, two candidate genes, including SCN9A, were neurons indicate that expression of these same PE mutations in tested (3). A missense mutation (L858H) in SCN9A was identified sympathetic ganglion neurons, that is, another cell type in which that segregated with the disease in a three-generation Chinese fam- Nav1.7 is normally expressed, leads to a reduction of excitability ily while an I848T mutation was present in a single sporadic case. in these cells (43). This occurs because Nav1.8 channels, which Both mutations affected conserved residues in the pore-forming a are relatively resistant to inactivation by depolarization and are subunit of the Nav1.7 channel, and multiple alignment indicated selectively expressed in addition to Nav1.7 in DRG neurons, are that the affected amino acids are conserved in sodium channels. not present within sympathetic ganglion neurons (43). These PE Subsequent independent studies confirmed these findings and mutations produce membrane depolarization due to an overlap identified missense mutations (mutations in which one amino between activation and steady-state inactivation, which inactivates acid is replaced by another) in individuals from all of the families sodium channels other than Nav1.8. The depolarization brings that had been examined in the original linkage study (4). To date, DRG neurons closer to the threshold of activation for the Nav1.8 nearly a dozen SCN9A mutations in multiple families have been channels that are present within DRG neurons, thus increasing identified as causing PE (5, 6, 36–41). Most of these mutations the excitability of these cells. But in sympathetic ganglion neurons, have been found in families from The Netherlands, the United which lack Nav1.8, the inactivation of the sodium channels results States, Belgium, France, Canada, and China, with a clear autoso- in reduced excitability. Introduction of Nav1.8 allows these cells to mal dominant inheritance pattern, although a few represent de fire action potentials, despite depolarization of resting membrane novo founder mutations (a mutation that arose in the DNA of an potential (43). This illustrates an important principle, that the individual several generations earlier and whom is considered to phenotype associated with a monogenic channelopathy is not pre- be a founder of a distinct population) (5, 6). dictable on the basis of the changes in physiology of the mutant All of the PE mutations detected to date are missense mutations sodium channel per se. The effect depends on the cell background that change important and highly conserved amino acid residues in which the mutant channel is expressed, so that physiological of the Nav1.7 protein. The majority of mutations that cause PE interactions that are specific to particular types of neurons (in the are located in cytoplasmic linkers of the Nav1.7 channel, but some case of PE, the physiological interaction of Nav1.7 and Nav1.8) may mutations (e.g., F216S and N395K) are located in transmembrane better explain the symptoms experienced by patients (45). These domains of the channel (Figure 1B). The PE mutations cause a data provide an explanation of why PE presents with pain due to

3606 The Journal of Clinical Investigation http://www.jci.org Volume 117 Number 12 December 2007 science in medicine hyperexcitability of nociceptors together with sympathetic dys- ages in the context of near-normal activation. These changes are function (flushing/erythema) that is at least in large part due to predicted to promote prolonged action potentials and repetitive hypoexcitability of sympathetic ganglion neurons (43). neuron firing in response to provoking stimuli, such as stretching and exposure to cold temperatures (7). The different effects of PE Paroxysmal extreme pain disorder mutations (which enhance channel activation) and PEPD muta- The condition first described in 1959 as rectal, ocular, and submax- tions (which impair channel inactivation) might contribute in part illary pain (46) has recently been renamed PEPD (OMIM 167400) to the different symptomatology in these two disorders. In either (47). PEPD is an autosomal dominant disorder characterized by case, these results are in keeping with the notion that Nav1.7 plays paroxysmal episodes (of sudden onset and increased intensity upon a critical role in modulation of the pain threshold. recurrence) of pain at different body sites, accompanied by skin flushing. There are four well-defined types of painful episodes. The Channelopathy-associated insensitivity to pain first occurs at birth with an archetypical red flush spread over the In contrast with PE and PEPD, CIP (OMIM 243000) is an autoso- buttocks and down the backs of the legs to the soles of the feet (48). mal recessive disorder (8, 53). Individuals with congenital indiffer- A second pattern involves rectal pain that is most evident in child- ence to pain have painless injuries beginning in infancy but other- hood and typically occurs at defecation, as a sudden (short-lived) wise normal sensory responses upon examination. Perception of onset of burning pain that moves down to the lower extremities passive movement, joint position, and vibration is normal, as are (47). The pain is followed by red discoloration of the skin of the tactile thresholds and light touch perception. There is intact ability pubic area, scrotum, perineum, buttocks, and the backs of both to distinguish between sharp and dull stimuli and to detect differ- legs and soles of the feet, lasting for about an hour. The ocular pat- ences in temperature. The insensitivity to pain does not appear to tern of pain is described as an intense burning sensation, lasting be due to axonal degeneration, as the nerves appear to be normal 30–60 seconds, followed by conjunctival injection (nonuniform upon gross examination (8). The complications of the disease fol- redness of the conjunctiva) and erythema of the eyelids and of the low the inability to feel pain, and most individuals will have inju- skin in the temporal region, lasting a few minutes (49, 50). Attacks ries to lip or tongue caused by biting themselves in the first 4 years may be precipitated by yawning and crying but also occur sponta- of life. Patients have frequent bruises and cuts, usually have a his- neously. Last, there is paroxysmal pain in the mandibular region tory of fractures that go unnoticed, and are often only diagnosed on both sides, with associated transient erythema of the overlying because of limping or lack of use of a limb. The literature contains skin, together with autonomic manifestations such as salivation, very colorful descriptions of patients with congenital inability to lacrimation (tearing), and rhinorrhoea (running nose). Symptoms perceive any form of pain. Individuals have been reported to walk may be induced in these subjects by the ingestion of cold drinks over burning coals and to place knives through their arms and drive or acidic or spicy foods. Moreover, these individuals are prone to spikes through a hand as part of crucifixion reenactment (8). a strange feeling of pressure or even a cramp-like sensation in the Cox et al. described 6 patients stemming from three consanguin- nose, following exposure of the face to bright sunlight or strong eous families of northern Pakistani origin (8). The highly inbred winds. In some patients, the painful crisis may be associated with population allowed for autozygosity mapping (homozygosity in nonepileptic tonic seizures and cardiac asystole (50). Carbamaze- which the two alleles are identical by descent), and a genome-wide pine, an antiepileptic drug, is effective in some patients, but high search led to the identification of a 20-cM homozygous region on dosages may be needed to achieve efficacy (51). A principal target of chromosome 2q24.3 with a maximum 2-point lod score of 3.2 (a anticonvulsant drugs in PEPD is most likely the sodium channels lod score of 3 or more is generally taken to indicate that 2 gene loci located in the peripheral sensory neuron (52). are close to each other on the chromosome; a lod score of 3 means A genome-wide linkage search in one large pedigree with PEPD the odds are a thousand to one in favor of genetic linkage). Further led to linkage to a region of chromosome 2q24.3 (7). Haplotype refinement of the region to 11.7 Mb was facilitated by addition of analysis identified several recombinants, which narrowed the criti- a third family. A bioinformatics approach suggested SCN9A as the cal region down to 16 cM. As this region contained SCN9A, the best candidate disease gene. Sequencing led to the identification of investigators sequenced this gene and identified eight heterozygous different homozygous mutations of SCN9A, and each family pos- missense mutations in eight families. All mutations were private, sessed a unique mutation. The mutations were identified in exon i.e., each family possessed a unique mutation. Interestingly, one 10 (S459X), exon 13 (I767X), and exon 15 (W897X) (8). All muta- individual was compound heterozygous for R996C and a de novo tions are nonsense mutations, that is, they change a codon that mutation (V1298D). This individual was more severely affected codes for one amino acid into a codon that does not specify any than his father. In another family in whom R996C was the only amino acid. These results were confirmed by two studies: one study mutation identified, there was a less severe phenotype. In five fam- in 9 western European and North and South American families ilies with typical PEPD, there were no SCN9A mutations found (7). (54) and another in a large Canadian family (55). Both studies used These findings are consistent with the genetic heterogeneity of PE linkage analysis, searched for homozygous haplotypes, identified and suggest locus heterogeneity in PEPD. the same gene, and detected 10 truncating SCN9A mutations. The Functional analysis of three mutations (I1461T, T1464I, and majority of affected patients were homozygous for SCN9A muta- M1627K) that are attributed to PEPD was carried out in transfec- tions, but 2 patients were compound heterozygous for different tion experiments using a cell-based assay in which a mutant sodi- SCN9A mutations (54). Functional studies show that CIP-associ- um channel was introduced into cells that normally do not express ated mutations cause loss of function of Nav1.7 (8, 55) (Figure 4). sodium channels (7). On the basis of these experiments, these This is in contrast with the genetic basis of PE and PEPD, in which mutations were reported to impair inactivation of the a subunit the disorders result from gain-of-function mutations. In DRG of the Nav1.7 channel (Figure 4). Steady-state inactivation was only neurons expressing mutant Nav1.7, the firing of action potentials partial in mutant channels and had shifted toward higher volt- was greatly impaired and comparable to background (8).

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Implications and questions of channel subtype specificity and thus inhibit many types of Collectively, the data from recent studies indicate that Nav1.7 sodium channels rather than selectively blocking Nav1.7 (52, 58). function is an essential and nonredundant requirement for noci- These agents, which act primarily through use-dependent blocks ception in humans. However, the genetic findings do not fully of sodium channels indeed are part of the armamentarium for the explain the clinical presentations described. Given the widespread treatment of many types of chronic pain, including some forms of expression of Nav1.7 throughout the sensory nervous system, it is neuropathic pain. Several of these drugs have shown a degree of remarkable that PE and PEPD have such different tissue distri- efficacy in patients with pain due to mutations in Nav1.7. Some butions of pain. Moreover, the variability in age of clinical onset PE patients have responded to oral mexiletine (600 mg daily) (60). remains unexplained. Also, although physiological studies have Interestingly, some PE mutations attenuate the inhibitory effect revealed a temperature-dependent shift that brings the activation on sodium channels of the sodium-channel blocker lidocaine, threshold of PE mutant channels close to that of wild-type Nav1.7 while other PE mutations do not, suggesting that the response to channels, possibly contributing to the alleviation of pain by cool- treatment with sodium-channel blockers in PE may depend on the ing in PE (56), the paroxysmal nature of the painful attacks in specific genotype (61). Carbamazepine is effective in some patients PE and PEPD is not fully understood. These observations argue with PEPD, as it stabilizes the inactivated state of sodium channels, that there may be factors other than the mutated Nav1.7 channel, meaning that fewer of these channels are available to open, mak- such as still–to be–identified binding partners (other protein mol- ing brain cells less excitable (7). In contrast, preliminary results in ecules that the channel interacts with, such as fibroblast growth PE indicate low or absent effectivity of this drug (62). Moreover, in factor homologous factors, which are known to modulate the those cases in which lidocaine or mexiletine are helpful in PE, the physiological properties of the sodium-channel isoforms) that are efficacy of these agents is only partial or transient (63). important in determining the topographic and temporal pattern In conclusion, these observations, while drawn from a small of these symptoms (57, 58). number of patients, suggest that blockade of voltage-gated sodi- The important role of mutations that change the sequence of um channels is a promising therapeutic option for the treatment SCN9A in various pain disorders suggests that SCN9A polymor- of pain but emphasize the need for the design of more highly phisms might contribute to intersubject variability in the sensation focused, Nav1.7-specific blockers or genetically tailored pharma- of pain in humans. This should encourage researchers to look for cological options for future testing. There will undoubtedly be SCN9A polymorphisms that are associated with chronic pain disor- progress along these lines in the future. ders other than PE and PEPD. It might also be expected that some SCN9A polymorphisms might confer protection against pain. Acknowledgments We thank the patients who participated in the studies that Implications for new therapeutic approaches to pain are described in this review. J.P.H. Drenth is a recipient of The Neuropathic pain in PE is therapeutically challenging (59). Indeed, Netherlands Organization for Health Research and Develop- Nav1.7 represents a target that might be inhibited by small mole- ment VIDI award research grant. S.G. Waxman is the recipi- cules in a subtype-specific or state-dependent manner during ecto- ent of grants from the Department of Veterans Affairs and the pic discharge, producing pain relief while sparing other neuronal Erythromelalgia Association. functions. The development of subtype selectivity of potentially therapeutically useful molecules has proven to be a challenge. Sev- Address correspondence to: Joost P.H. Drenth, Department of eral classes of drugs, including local anesthetics (e.g., lidocaine), Medicine, Division of Gastroenterology and Hepatology, Univer- systemic antiarrhythmics (e.g., mexiletine), and antiepileptic drugs sity Medical Center St. Radboud, PO Box 9101, 6500 HB Nijme- such as phenytoin or carbamazepine, target sodium channels and gen, The Netherlands. Phone: 31-24-3614760; Fax: 31-24-3540103; act as channel blockers, although they do not show a high degree E-mail: [email protected].

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